EP1468998A1 - Kristallines Monohydrat von Tiotropiumbromid und Verfahren zu dessen Herstellung. - Google Patents
Kristallines Monohydrat von Tiotropiumbromid und Verfahren zu dessen Herstellung. Download PDFInfo
- Publication number
- EP1468998A1 EP1468998A1 EP04016877A EP04016877A EP1468998A1 EP 1468998 A1 EP1468998 A1 EP 1468998A1 EP 04016877 A EP04016877 A EP 04016877A EP 04016877 A EP04016877 A EP 04016877A EP 1468998 A1 EP1468998 A1 EP 1468998A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tiotropium bromide
- crystalline
- bromide monohydrate
- preparation
- monohydrate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/16—Central respiratory analeptics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the invention relates to a crystalline monohydrate of (1 ⁇ , 2 ⁇ , 4 ⁇ , 5 ⁇ , 7 ⁇ ) -7 - [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0 2 , 4 ] nonane bromide, process for its preparation, and its use for the preparation of a medicament, in particular for the production of a medicament with anticholinergic activity.
- tiotropium bromide is preferably carried out by inhalation.
- suitable inhalable powders which can be introduced into suitable capsules (inhalettes) bottled be applied by means of appropriate powder inhalers are used come.
- an inhalative application by application appropriate inhalation aerosols done. These include powdered Inhalation aerosols, for example, HFA134a, HFA227 or their mixture as Propellant gas included.
- Proper preparation of the aforementioned compositions useful for the inhalative administration of a drug relies on various parameters associated with the nature of the drug itself. Without limitation, examples of these parameters are the effective stability of the starting material under various environmental conditions, stability in the course of preparation of the pharmaceutical formulation, and stability in the final compositions of the drug.
- the drug used to make the above drug compositions should be as pure as possible, and its long term storage stability must be ensured under various environmental conditions. This is absolutely necessary in order to prevent the use of pharmaceutical compositions in which, in addition to the actual active substance, for example, decomposition products thereof are contained. In such a case, an active ingredient content found in capsules could be lower than specified.
- the absorption of moisture reduces the content of drug due to the increase in weight caused by the absorption of water.
- Moisture-prone drugs must be protected from moisture during storage, for example by adding suitable drying agents or by storing the drug in a humidity protected environment.
- the ingestion of moisture may reduce the level of drug during manufacture if the drug is exposed to the environment without any protection from moisture.
- Uniform distribution of the drug in the formulation is a critical factor, especially if low dosage of the drug is required.
- Another aspect which is significant in the case of inhalation substances to be applied by means of a powder is due to the fact that only particles of a certain particle size enter the lung during the content of the substance.
- the particle size of these respirable particles (inhalable fraction) is in the submicron range.
- a milling process is also required.
- Another problem during the grinding process to produce the desired Drug formulation may occur as a result of this process Energy input and the load on the surface of the crystals. This can be done under Circumstances to polymorphic changes, to a transformation to amorphous Shape or lead to a change of the crystal lattice.
- the pharmaceutical grade of a drug formulation always the same crystalline Morphology of the drug must be guaranteed, are also ahead of this Background to the stability and properties of the crystalline drug increased To make demands.
- the stability of a drug is further in drug compositions important for determining the period of validity of the specialty drug; this duration is the one during which the drug is administered without any risk can be.
- a high stability of a drug in the aforementioned Pharmaceutical compositions under various storage conditions Therefore, for both the patients as well as for the manufacturer another advantage represents.
- the object of the invention is thus to provide a new, stable Crystal form of the compound tiotropium bromide corresponding to the abovementioned high Requirements to be met by a drug substance are sufficient.
- the present invention relates to crystalline Tiotropium bromide monohydrate.
- Another aspect of the present invention relates to a manufacturing method of crystalline hydrates of tiotropium bromide.
- This manufacturing method is characterized characterized in that tiotropium bromide, which, for example, after the in EP 418 716 A1 as disclosed in water is received, the resulting mixture is heated and finally the Hydrates of Tiotropiumbromids are crystallized with slow cooling.
- the present invention further relates to crystalline hydrates of tiotropium bromide, which are obtainable by the above procedure.
- One aspect of the present invention relates to a method of producing crystalline tiotropium bromide monohydrate, which will be described in more detail below.
- crystalline monohydrate according to the present invention, it is necessary to take up tiotropium bromide, which has been obtained, for example, according to the preparation procedure disclosed in EP 418 716 A1, in water, to heat, to carry out a purification with activated carbon and, after separating off the activated carbon under a slow flow Cool the tiotropium bromide monohydrate slowly to crystallize.
- the preferred procedure according to the invention is as described below.
- the solvent is mixed with tiotropium bromide, which has been obtained, for example, according to the preparation procedure disclosed in EP 418 716 A1.
- tiotropium bromide which has been obtained, for example, according to the preparation procedure disclosed in EP 418 716 A1.
- 0.4 to 1.5 kg, preferably 0.6 to 1 kg, particularly preferably about 0.8 kg of water are used as solvents per mole of tiotropium bromide used.
- the resulting mixture is heated with stirring, preferably to more than 50 ° C, more preferably to more than 60 ° C.
- the maximum selectable temperature is determined by the boiling point of the solvent used water.
- the mixture is heated to a range of 80-90 ° C.
- Activated carbon, dry or moist with water, is introduced into this solution.
- the activated carbon is slurried in water before introduction into the tiotropium bromide-containing solution. 70 to 200 g, preferably 100 to 160 g, particularly preferably about 135 g of water are used for slurrying the activated carbon per tiotropium bromide used. If the activated carbon is slurried in water prior to introduction into the tiotropium bromide-containing solution, it is advisable to rinse with the same amount of water.
- stirring is continued for 5 to 60 minutes, preferably for 10 to 30 minutes, more preferably for about 15 minutes after the activated carbon has been added, and the resulting mixture is filtered to remove the activated carbon.
- the filter is then rinsed with water.
- 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water are used per mole of tiotropium bromide used.
- the filtrate is then cooled slowly, preferably to a temperature of 20-25 ° C.
- the cooling is preferably carried out at a cooling rate of 1 to 10 ° C per 10 to 30 minutes, preferably 2 to 8 ° C per 10 to 30 minutes, more preferably 3 to 5 ° C per 10 to 20 minutes, most preferably 3 up to 5 ° C per approx. 20 minutes.
- a cooling rate of 1 to 10 ° C per 10 to 30 minutes, preferably 2 to 8 ° C per 10 to 30 minutes, more preferably 3 to 5 ° C per 10 to 20 minutes, most preferably 3 up to 5 ° C per approx. 20 minutes.
- After cooling to 20 to 25 ° C further cooling to below 20 ° C, particularly preferably 10 to 15 ° C followed.
- After cooling is stirred between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, more preferably about one hour to complete the crystallization.
- the resulting crystals are finally isolated by filtration or suction of the solvent. Should it be necessary to subject the crystals obtained to a further washing step, it is advisable to use water or acetone as the washing
- 0.1 to 1.0 L, preferably 0.2 to 0.5 L, particularly preferably about 0.3 L of solvent can be used per mole of tiotropium bromide used to wash the resulting tiotropium bromide monohydrate crystals.
- the washing step may be repeated.
- the product obtained is dried in vacuo or by means of heated circulating air until a water content of 2.5-4.0% is reached.
- One aspect of the present invention relates to crystalline tiotropium bromide monohydrate, which is obtainable according to the procedure described above is.
- the tiotropium bromide monohydrate obtainable according to the procedure described above was subjected to examination by DSC (Differential Scanning Calorimetry).
- the DSC diagram has two characteristic signals. The first, relatively broad, endothermic signal between 50-120 ° C is due to the dehydration of Tiotropiumbomid monohydrate to anhydrous form. The second, relatively sharp, endothermic maximum at 230 ⁇ 5 ° C is attributable to the melting of the substance ( Figure 1).
- These data were obtained using a Mettler DSC 821 and evaluated with the Mettler STAR software package. The data were collected at a heating rate of 10 K / min.
- the present invention is directed to crystalline tiotropium bromide monohydrate which according to Firgur 1 is characterized by an endothermic peak at 230 ° C ( ⁇ 5 ° C) at a heating rate of 10K / min.
- the tiotropium bromide monohydrate according to the invention was characterized by means of IR spectroscopy.
- the data was collected using a Nicolet FTIR spectrometer and evaluated using the Nicolet OMNIC software version 3.1 software. The measurement was carried out with 2.5 ⁇ mol tiotropium bromide monohydrate in 300 mg KBr.
- the present invention relates to crystalline tiotropium bromide monohydrate which, according to Firgur 2, is characterized by an IR spectrum exhibiting, inter alia, wavenumbers 3570, 3410, 3105, 1730, 1260, 1035 and 720 cm -1 bands.
- the tiotropium bromide monohydrate according to the invention was characterized by X-ray structure analysis.
- the X-ray diffraction intensity measurements were performed on an AFC7R-4 circular diffractometer (Rigaku) using monochromatized copper K ⁇ radiation.
- the structural solution and refinement of the crystal structure was carried out by direct methods (program SHELXS86) and FMLQ-Vefeintechnik (program TeXsan). Experimental details on crystal structure, structure solution and refinement are summarized in Table 2.
- a further aspect of the present invention relates to the use of tiotropium bromide monohydrate as a medicament due to the pharmaceutical activity of the hydrate according to the invention.
- a medicament which can be administered by inhalation in particular an inhalable powder which contains the crystalline tiotropium bromide monohydrate described by the present invention, it is possible to proceed according to methods known in the prior art.
- another aspect of the present invention is directed to inhalation powders characterized by a content of tiotropium bromide monohydrate.
- another aspect of the present invention is directed to the use of tiotropium bromide monohydrate for the manufacture of a medicament for the treatment of diseases in which the application of an anticholinergic agent can produce a therapeutic benefit.
- Preferred is the corresponding use for the manufacture of a medicament for the treatment of asthma or COPD.
- tiotropium bromide 15.0 kg are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the tiotropium bromide-containing solution and rinsed with 4.3 kg of water. The resulting mixture is stirred for at least 15 minutes at 80-90 ° C and then filtered through a heated filter in a pre-heated to 70 ° C jacket temperature apparatus. The filter is rinsed with 8.6 kg of water.
- the contents of the apparatus are cooled at 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is further cooled to 10-15 ° C and the crystallization is completed by at least one hour stirring.
- the crystals are isolated on a Nutschentrockner, washed the isolated crystal slurry with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The resulting crystals are dried at 25 ° C for 2 hours in a stream of nitrogen. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicinal Preparation (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE10050621 | 2000-10-12 | ||
DE10050621 | 2000-10-12 | ||
EP01983510A EP1326862B1 (de) | 2000-10-12 | 2001-09-28 | Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01983510A Division EP1326862B1 (de) | 2000-10-12 | 2001-09-28 | Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1468998A1 true EP1468998A1 (de) | 2004-10-20 |
Family
ID=7659568
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01983510A Expired - Lifetime EP1326862B1 (de) | 2000-10-12 | 2001-09-28 | Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
EP04016877A Withdrawn EP1468998A1 (de) | 2000-10-12 | 2001-09-28 | Kristallines Monohydrat von Tiotropiumbromid und Verfahren zu dessen Herstellung. |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP01983510A Expired - Lifetime EP1326862B1 (de) | 2000-10-12 | 2001-09-28 | Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels |
Country Status (47)
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8759369B2 (en) | 2007-07-09 | 2014-06-24 | Norton Healthcare Ltd. | Inhalable solid amorphous particles comprising tiotropium bromide and a co-solid |
US9655969B2 (en) | 2011-12-19 | 2017-05-23 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
US10034866B2 (en) | 2014-06-19 | 2018-07-31 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL208137B1 (pl) * | 2001-06-22 | 2011-03-31 | Boehringer Ingelheim Pharma | Bezwodny krystaliczny bromek tiotropium, sposób jego wytwarzania i zastosowanie krystalicznego monohydratu bromku tiotropium do wytwarzania krystalicznego bezwodnego bromku tiotropium |
US6608055B2 (en) | 2001-06-22 | 2003-08-19 | Boehringer Ingelheim Pharma Kg | Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition |
DE10212264A1 (de) | 2002-03-20 | 2003-10-02 | Boehringer Ingelheim Pharma | Kristallines Mikronisat, Verfahren zu dessen Herstellung und dessen Verwendung zur Herstellung eines Arzneimittels |
DE10214263A1 (de) * | 2002-03-28 | 2003-10-16 | Boehringer Ingelheim Pharma | HFA-Suspensionsformulierungen enthaltend ein Anticholinergikum |
US7244415B2 (en) | 2002-03-28 | 2007-07-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations of an anhydrate |
US7311894B2 (en) | 2002-03-28 | 2007-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | HFA suspension formulations containing an anticholinergic |
US7056916B2 (en) | 2002-11-15 | 2006-06-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Medicaments for the treatment of chronic obstructive pulmonary disease |
DE10317461A1 (de) | 2003-04-16 | 2004-10-28 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Radioaktiv markierte Mikropartikel, Verfahren zu deren Herstellung und deren Verwendung |
DK1682542T3 (da) * | 2003-11-03 | 2010-05-10 | Boehringer Ingelheim Int | Nyt krystallinsk anhydrat med anticholinerg effekt |
ES2422730T3 (es) * | 2003-11-03 | 2013-09-13 | Boehringer Ingelheim Int | Sales de tiotropio, procedimiento para su preparación, así como formulaciones de medicamentos que las contienen |
US7968717B2 (en) | 2003-11-03 | 2011-06-28 | Boehringer Ingelhein International Gmbh | Crystalline anhydrate with anticholinergic efficacy |
PT1682541E (pt) | 2003-11-03 | 2010-04-14 | Boehringer Ingelheim Int | Processo para a preparação de sais de tiotrópio |
DE102004016179A1 (de) * | 2004-03-30 | 2005-10-20 | Boehringer Ingelheim Pharma | Verbindungen zur Behandlung von proliferativen Prozessen |
AU2005235419B2 (en) | 2004-04-22 | 2010-11-04 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations containing benzoxazine for treating respiratory diseases |
US7220742B2 (en) | 2004-05-14 | 2007-05-22 | Boehringer Ingelheim International Gmbh | Enantiomerically pure beta agonists, process for the manufacture thereof and use thereof as medicaments |
DE102004024454A1 (de) | 2004-05-14 | 2005-12-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Enantiomerenreine Betaagonisten, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel |
ES2322148T3 (es) | 2004-08-11 | 2009-06-17 | BOEHRINGER INGELHEIM PHARMA GMBH & CO. KG | Medicamentos que contienen anticolinergicos para el tratamiento en las vias urinarias. |
US20060079544A1 (en) * | 2004-08-13 | 2006-04-13 | Boehringer Ingelheim International Gmbh | Medicaments for the prevention or treatment of alveolar pneumonia comprising an anticholinergic |
DE102004048389A1 (de) | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Modifizierung von Oberflächen von Laktose als Hilfsstoff zur Verwendung für Pulverinhalativa |
MX2007004768A (es) * | 2004-10-21 | 2007-05-10 | Boehringer Ingelheim Int | Blister para inhaladores. |
JP2008532973A (ja) * | 2005-03-09 | 2008-08-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 抗コリン作用薬とpde5−阻害剤に基づく新規な医薬組成物 |
WO2006111549A1 (de) | 2005-04-21 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Dihydrothienopyrimidine zur behandlung von entzündlichen erkrankungen |
MX2007012907A (es) | 2005-04-28 | 2008-03-14 | Boehringer Ingelheim Int | Nuevos compuestos para el tratamiento de enfermedades inflamatorias. |
EP2085396A3 (en) | 2005-05-02 | 2009-11-25 | Boehringer Ingelheim International Gmbh | Novel crystalline forms of tiotropium bromide |
CN101203513A (zh) * | 2005-05-02 | 2008-06-18 | 贝林格尔·英格海姆国际有限公司 | 噻托溴铵的晶型 |
MX2007015997A (es) * | 2005-06-15 | 2008-03-07 | Boehringer Ingelheim Int | Procedimiento para preparar nuevas sales de tiotropio, nuevas sales de tiotropio como tales y composiciones farmaceuticas de las mismas. |
DE102005030733A1 (de) | 2005-07-01 | 2007-01-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Arzneimittelkombinationen zur Behandlung von Atemwegserkrankungen enthaltend langwirksame Beta-2-Agonisten und wenigstens einen weiteren Wirkstoff |
AU2006277968A1 (en) * | 2005-08-06 | 2007-02-15 | Boehringer Ingelheim International Gmbh | Use of tiotropium salts in the treatment of severe persistant asthma |
BRPI0614410A2 (pt) | 2005-08-15 | 2011-03-29 | Boehringer Ingelheim Int | processo para preparação de betamiméticos |
US20070086957A1 (en) | 2005-10-10 | 2007-04-19 | Thierry Bouyssou | Combination of medicaments for the treatment of respiratory diseases |
US7423146B2 (en) | 2005-11-09 | 2008-09-09 | Boehringer Ingelheim International Gmbh | Process for the manufacturing of pharmaceutically active 3,1-benzoxazine-2-ones |
DE102005059602A1 (de) | 2005-12-14 | 2007-06-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verfahren zur Mikronisierung |
TW200734333A (en) * | 2005-12-19 | 2007-09-16 | Sicor Inc | Pure and stable tiotropium bromide |
EP2123650B1 (en) | 2005-12-19 | 2012-04-04 | Sicor, Inc. | Novel form of tiotropium bromide and process for preparation thereof |
WO2007077162A1 (en) * | 2006-01-04 | 2007-07-12 | Boehringer Ingelheim International Gmbh | Use of tiotropium salts in the treatment of moderate persistent asthma |
EP1847543A1 (de) | 2006-04-19 | 2007-10-24 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dihydrothienopyrimidine zur Behandlung von entzündlichen Erkrankungen |
US20080051582A1 (en) | 2006-07-10 | 2008-02-28 | Sicor Inc. | Process for the preparation of tiotropium bromide |
CA2660186A1 (en) | 2006-08-07 | 2008-02-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical combinations for the treatment of respiratory diseases |
PE20080610A1 (es) | 2006-08-22 | 2008-07-15 | Boehringer Ingelheim Int | Nuevos beta-agonistas enantiomericamente puros, procedimientos para su preparacion y uso como medicamentos |
EP1923393A1 (en) * | 2006-11-17 | 2008-05-21 | Boehringer Ingelheim Pharma GmbH & Co. KG | Crystalline form of tiotropium bromide and urea |
EP1925295A1 (de) * | 2006-11-22 | 2008-05-28 | Boehringer Ingelheim Pharma GmbH & Co. KG | Stabile Pulverformulierung enthaltend ein Anticholinergikum |
ES2381452T3 (es) | 2007-10-19 | 2012-05-28 | Boehringer Ingelheim International Gmbh | PIPERIDINO-DIHIDROTIENOPIRIMIDINAS sustituidas |
EP2093219A1 (de) | 2008-02-22 | 2009-08-26 | Boehringer Ingelheim International Gmbh | Kristalline, enantiomerenreine Salzform eines Betamimetikums und dessen Verwendung als Arzneimittel |
WO2010011813A1 (en) * | 2008-07-23 | 2010-01-28 | Alkermes, Inc. | Complex of trospium and pharmaceutical compositions thereof |
BRPI0923051B1 (pt) | 2008-12-19 | 2022-07-19 | Centrexion Therapeutics Corporation | Pirimidin-4-carboxamidas cíclicas como antagonistas do receptor de ccr2 para o tratamento de inflamação, asma e copd, seu uso, formulação e combinação farmacêutica que os compreende |
EP2201934A1 (en) | 2008-12-23 | 2010-06-30 | CHIESI FARMACEUTICI S.p.A. | Tiotropium aerosol formulation products with improved chemical stability |
WO2010101538A2 (en) | 2009-03-06 | 2010-09-10 | Bilgic Mahmut | New crystal forms |
IN2012DN00968A (tr) | 2009-08-07 | 2015-04-10 | Generics Uk Ltd | |
WO2011015883A1 (en) | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Dichloromethane solvate of tiotropium bromide and its use |
PT2513093E (pt) | 2009-12-17 | 2014-10-22 | Boehringer Ingelheim Int | Novos antagonistas do receptor ccr2 e suas utilizações |
JP5658272B2 (ja) | 2009-12-17 | 2015-01-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2の新規アンタゴニスト及びこれらの使用 |
CA2786245A1 (en) | 2010-01-29 | 2011-08-04 | Boehringer Ingelheim International Gmbh | Substituted naphthyridines and their use as syk kinase inhibitors |
EP2569298B1 (en) | 2010-05-12 | 2015-11-25 | Boehringer Ingelheim International GmbH | Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments |
JP5646736B2 (ja) | 2010-05-12 | 2014-12-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ccr2受容体アンタゴニスト、これらの製造方法、及び薬物としてのこれらの使用 |
JP5647339B2 (ja) | 2010-05-17 | 2014-12-24 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | Ccr2アンタゴニスト及びこれらの使用 |
US9018212B2 (en) | 2010-05-25 | 2015-04-28 | Boehringer Ingelheim International Gmbh | Pyridazine carboxamides as CCR2 receptor antagonists |
JP5721242B2 (ja) | 2010-06-01 | 2015-05-20 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 新規ccr2アンタゴニスト |
JP5959537B2 (ja) | 2011-01-28 | 2016-08-02 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 置換ピリジニル−ピリミジン及び医薬としてのその使用 |
TR201102068A2 (tr) * | 2011-03-03 | 2012-09-21 | Bi̇lgi̇ç Mahmut | Tiotropyum bromür içeren kristal maddeler |
WO2012171863A1 (en) | 2011-06-16 | 2012-12-20 | Boehringer Ingelheim International Gmbh | New selective ccr2 antagonists |
WO2013010839A1 (en) | 2011-07-15 | 2013-01-24 | Boehringer Ingelheim International Gmbh | Novel and selective ccr2 antagonists |
EP2736886B1 (en) | 2011-07-26 | 2016-09-14 | Boehringer Ingelheim International GmbH | Substituted quinolines and their use as medicaments |
US20130059866A1 (en) | 2011-08-24 | 2013-03-07 | Boehringer Ingelheim International Gmbh | Novel piperidino-dihydrothienopyrimidine sulfoxides and their use for treating copd and asthma |
CZ304368B6 (cs) * | 2011-11-28 | 2014-04-02 | Zentiva, K.S. | Směsný solvát tiotropium bromidu a způsob jeho přípravy |
US9096579B2 (en) | 2012-04-20 | 2015-08-04 | Boehringer Ingelheim International Gmbh | Amino-indolyl-substituted imidazolyl-pyrimidines and their use as medicaments |
EP2914593B1 (en) | 2012-11-05 | 2017-01-11 | Zentiva, k.s. | Stabilization of tiotropium solvates |
EP2913332A1 (en) * | 2014-02-27 | 2015-09-02 | Euticals S.P.A. | Crystalline form of tiotropium bromide with lactose |
EP3119766B1 (en) | 2014-03-19 | 2019-05-22 | Boehringer Ingelheim International GmbH | Heteroaryl syk inhibitors |
RU2567539C1 (ru) * | 2015-02-04 | 2015-11-10 | Индивидуальный предприниматель Михайлов Олег Ростиславович | КРИСТАЛЛИЧЕСКАЯ γ-МОДИФИКАЦИЯ (1α,2β,4β,5α,7β-7)-[(ГИДРОКСИДИ-2-ТИЕНИЛАЦЕТИЛ)ОКСИ]-9,9-ДИМЕТИЛ-3-ОКСА-9-АЗОНИАТРИЦИКЛО[3.3.1.02,4]НОНАН БРОМИДА МОНОГИДРАТА, СПОСОБ ЕЁ ПОЛУЧЕНИЯ И ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ НА ЕЁ ОСНОВЕ |
WO2017138896A1 (en) | 2016-02-11 | 2017-08-17 | Sima Patent Ve Lisanslama Hizmetleri Ltd. Şti | Crystalline form of tiotropium bromide anhydrate |
EP3430011A4 (en) * | 2016-11-04 | 2019-08-14 | Sima Patent Ve Lisanslama Hizmetleri Ltd. STI | NOVEL ACTIVE SUBSTANCE |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418716A1 (de) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Neue Thienylcarbonsäureester von Aminoalkoholen, ihre Quaternierungsprodukte sowie die Herstellung und Verwendung dieser Verbindungen |
WO1994013262A1 (en) * | 1992-12-09 | 1994-06-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations |
WO2000007567A1 (de) * | 1998-08-04 | 2000-02-17 | Jago Research Ag | Medizinische aerosolformulierungen |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19834506A1 (de) * | 1998-07-31 | 2000-02-03 | Hexal Ag | Transmucosales therapeutisches System zur Anwendung von Sildenafil |
-
2001
- 2001-09-28 PL PL366041A patent/PL207870B1/pl unknown
- 2001-09-28 EA EA200300457A patent/EA004381B1/ru not_active IP Right Cessation
- 2001-09-28 AT AT01983510T patent/ATE276253T1/de active
- 2001-09-28 PT PT01983510T patent/PT1326862E/pt unknown
- 2001-09-28 AU AU2002214996A patent/AU2002214996B2/en not_active Expired
- 2001-09-28 NZ NZ525733A patent/NZ525733A/en not_active IP Right Cessation
- 2001-09-28 TR TR2004/02579T patent/TR200402579T4/tr unknown
- 2001-09-28 EP EP01983510A patent/EP1326862B1/de not_active Expired - Lifetime
- 2001-09-28 CZ CZ20031025A patent/CZ301841B6/cs not_active IP Right Cessation
- 2001-09-28 IL IL15533501A patent/IL155335A0/xx active IP Right Grant
- 2001-09-28 DZ DZ013478A patent/DZ3478A1/fr active
- 2001-09-28 SI SI200130219T patent/SI1326862T1/xx unknown
- 2001-09-28 JP JP2002534314A patent/JP3764422B2/ja not_active Expired - Lifetime
- 2001-09-28 WO PCT/EP2001/011225 patent/WO2002030928A1/de active IP Right Grant
- 2001-09-28 OA OA1200300107A patent/OA12403A/fr unknown
- 2001-09-28 ES ES01983510T patent/ES2228965T3/es not_active Expired - Lifetime
- 2001-09-28 EE EEP200300171A patent/EE04567B1/xx unknown
- 2001-09-28 SK SK436-2003A patent/SK287009B6/sk not_active IP Right Cessation
- 2001-09-28 EP EP04016877A patent/EP1468998A1/de not_active Withdrawn
- 2001-09-28 ME MEP-2008-400A patent/ME00243B/me unknown
- 2001-09-28 RS YU27303A patent/RS50218B/sr unknown
- 2001-09-28 AP APAP/P/2003/002775A patent/AP1572A/en active Active
- 2001-09-28 ME MEP-400/08A patent/MEP40008A/xx unknown
- 2001-09-28 DE DE50103666T patent/DE50103666D1/de not_active Expired - Lifetime
- 2001-09-28 CA CA002425539A patent/CA2425539C/en not_active Expired - Lifetime
- 2001-09-28 BR BR0114584-3A patent/BR0114584A/pt active Pending
- 2001-09-28 CN CNB018171435A patent/CN1221549C/zh not_active Ceased
- 2001-09-28 CN CNB2005100977370A patent/CN100519558C/zh not_active Ceased
- 2001-09-28 GE GE5214A patent/GEP20063905B/en unknown
- 2001-09-28 KR KR1020037005083A patent/KR100823860B1/ko active IP Right Grant
- 2001-09-28 AU AU1499602A patent/AU1499602A/xx active Pending
- 2001-09-28 DK DK01983510T patent/DK1326862T3/da active
- 2001-09-28 MX MXPA03003221A patent/MXPA03003221A/es active IP Right Grant
- 2001-09-28 HU HU0301022A patent/HU226830B1/hu unknown
- 2001-09-28 UA UA2003054185A patent/UA74215C2/uk unknown
- 2001-10-02 SA SA01220412A patent/SA01220412B1/ar unknown
- 2001-10-09 EG EG20011058A patent/EG24142A/xx active
- 2001-10-09 TW TW090124963A patent/TW589313B/zh active
- 2001-10-10 MY MYPI20014705A patent/MY126931A/en unknown
- 2001-10-10 UY UY26962A patent/UY26962A1/es not_active Application Discontinuation
- 2001-10-10 PE PE2001001000A patent/PE20020422A1/es active IP Right Grant
- 2001-10-12 AR ARP010104782A patent/AR034389A1/es active Pending
-
2003
- 2003-03-26 CR CR6938A patent/CR6938A/es unknown
- 2003-03-28 BG BG107687A patent/BG66161B1/bg active Active
- 2003-03-31 ZA ZA200302500A patent/ZA200302500B/en unknown
- 2003-04-07 EC EC2003004540A patent/ECSP034540A/es unknown
- 2003-04-08 MA MA27102A patent/MA25842A1/fr unknown
- 2003-04-09 IS IS6772A patent/IS2339B/is unknown
- 2003-04-10 HR HR20030276A patent/HRP20030276B1/xx not_active IP Right Cessation
- 2003-04-10 IL IL155335A patent/IL155335A/en unknown
- 2003-04-11 NO NO20031694A patent/NO328465B1/no not_active IP Right Cessation
-
2004
- 2004-05-20 HK HK04103583A patent/HK1060567A1/xx not_active IP Right Cessation
-
2006
- 2006-06-07 HK HK06106478.2A patent/HK1086557A1/xx not_active IP Right Cessation
-
2008
- 2008-09-19 AR ARP080104109A patent/AR068527A2/es unknown
-
2013
- 2013-07-11 UY UY34901A patent/UY34901A/es not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0418716A1 (de) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Neue Thienylcarbonsäureester von Aminoalkoholen, ihre Quaternierungsprodukte sowie die Herstellung und Verwendung dieser Verbindungen |
WO1994013262A1 (en) * | 1992-12-09 | 1994-06-23 | Boehringer Ingelheim Pharmaceuticals, Inc. | Stabilized medicinal aerosol solution formulations |
WO2000007567A1 (de) * | 1998-08-04 | 2000-02-17 | Jago Research Ag | Medizinische aerosolformulierungen |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8759369B2 (en) | 2007-07-09 | 2014-06-24 | Norton Healthcare Ltd. | Inhalable solid amorphous particles comprising tiotropium bromide and a co-solid |
US9655969B2 (en) | 2011-12-19 | 2017-05-23 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
US10034866B2 (en) | 2014-06-19 | 2018-07-31 | Teva Branded Pharmaceutical Products R&D, Inc. | Inhalable medicament comprising tiotropium |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1326862B1 (de) | Kristallines monohydrat von tiotropiumbromid, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels | |
EP1401445B1 (de) | Kristallines anticholinergikum, verfahren zu dessen herstellung und dessen verwendung zur herstellung eines arzneimittels | |
US6777423B2 (en) | Crystalline tiotropium bromide monohydrate, processes for the preparation thereof, and pharmaceutical compositions | |
US6608055B2 (en) | Crystalline anticholinergic, processes for preparing it and its use for preparing a pharmaceutical composition | |
EP1487832B1 (de) | Kristallines mikronisat des tiotropiumbromids | |
EP1379220B1 (de) | Inhalationskapseln | |
EP2083007B1 (de) | Tiotropiumsalze, Verfahren zu deren Herstellung sowie diese enthaltende Arzneimittelformulierungen | |
DE10153737A1 (de) | Kristallines Natriumsalz des Telmisartans, Verfahren zu dessen Herstellung und dessen Verwendung zur Herstellung eines Arzneimittels | |
EP1682541B1 (de) | Verfahren zur herstellung von tiotropiumsalzen | |
EP1695701B1 (de) | HFA-Suspensionsformulierungen enthaltend ein Anticholinergikum | |
WO2003082244A2 (de) | Hfa-suspensionsformulierungen eines anhydrats |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
AC | Divisional application: reference to earlier application |
Ref document number: 1326862 Country of ref document: EP Kind code of ref document: P |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK RO SI |
|
17P | Request for examination filed |
Effective date: 20050420 |
|
AKX | Designation fees paid |
Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR |
|
AXX | Extension fees paid |
Extension state: SI Payment date: 20050420 Extension state: RO Payment date: 20050420 Extension state: MK Payment date: 20050420 Extension state: LV Payment date: 20050420 Extension state: LT Payment date: 20050420 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Effective date: 20060124 |